Process of making xanthin derivatives.



, homologues of xanthin, which have bound to No. meta UNITED STATESPatented A ril 12, 190 i.

PATENT OFFICE.-

MITFORD C. MASSIE, OF WASHINGTON, DISTRICT OF COLUMBIA, ADMIN- ISTRATOROF, FRITZ AOH, DECEASED, ASSIGNORTO (J. F. BOEHRINGER & SOEHNE, OFMANNHEIM-WALDHOF, GERMANY, A FIRM.

PROCESS OF MAKING X A NTHIN DERIVATIVES SPEGIFICATION forming part ofLetters Patent No. 757,329, dated April 12, 1904. Application filedFebruary '7, 1903. Serial No. 142,590. (No specimens.) I

To aZZ whmn it wea concern: I

Be it known that FRITZ Acn, deceased, late a citizen of Germany, and aresident of Mannheim, Germany, did invent new and useful Improvements inthe Preparation of Xanthin Derivatives; and I, MITFORD O. MASSIE, theduly-constituted administrator of the estate of said FRITZ AoII,deceased, do hereby declare the following to be a full, clear, and exactdescription of the said invention of said decedent, such as will enableothers skilled in the art to which it appertains to make and use thesame.

This invention relates to the art of preparing Xanthins or Xanthinderivatives, such as cafiein, theobromin; and the object of the same isto utilize the alkyl-Xanthin derivatives having a methyl group bound tothe carbon atom at the position 8 according to the nomenclatureadoptedby Emil Fischer and explained, e. g., in United States Patent No.607,028, dated July 12, 1898.

In United States Patent No. 667,381, dated February 5, 1901, and inGerman Patent No. 128,212, issued February 8, 1902, is described a classof derivatives, or, more specifically,

the carbon atom in the position 8 of the purinring a methyl group andwhich are therefore identified by the general structural formula:

R.ll I (f0 00 O on the property of S-trichloroalkyl-xanthin, whichconstitutes a part of the subject-matter of this inventors application,Serial No.

142,589, filed February 7 1903, (Case G',) of releasing the 0013 groupbound to the O atom in the position 8 when properly treated, therebygiving rise to a dechlorized Xanthin derivative. If these trichloroderivatives are boiled with water for a sustained period of time,carbonic acid is evolved and hydrochloric acid formed, giving rise tothe reaction expressed in the following equation: R.NCO

| I R 00 CN. +2HO= RN-CO l I R 00 C-N +CO2+3HCI (1H RN-O N V In thismanner caflein may be obtained from 8-trichloromethyl Xanthin, and,generally speaking, all of the 8-trichloromethyl-xanthins thus farexamined have reacted in this way-that is to say, have replaced theC013- group by a hydrogen atom.

In order to make afull disclosure of this invention, the method ofmanufacturing and the properties of the starting materials employed incarrying out the invention will first be described and then will begiven in detail a number of examples of what is considered the preferredmanner of practicing the said invention.

Ema/mple 1-Pre10amti0n 0 f Theobromnfrom 8- Trio/iZoromet/tyZt/mobro-mm.

The starting material for this process, the

S-trichloromethyltheobromin, together withtemperature.

dissolved one hundred andthirty grams of chlorin. This mixture is thenconstantly shaken or agitated for four hours at ordinary The chlorin isthereby caused to gradually disappear by' combining with the theobrominderivative, and the greater portion of the suspended matter graduallygoes into solution. The whole is thereupon placed on the filter toseparate thesmall amount of unchanged methyltheobromin, and the filtrateis thereupon subjected to evaporation in cacao su'fiicient to drive offthe phosphorous oxychlorid and to leave the new resultant body,- the8-trichloromethyltheobromin or 3 7 dimethyl 8 trichloro-methyl-xanthin,as a residue Which is purified by dissolving in acetic ether andcrystallizing therefrom. The crystals thus obtained are in the form ofshining prisms, which contain acetic ether of crystallization, saidacetic ether being, however, readily and gradually dissipated whendrying the crystals in the air This new xanthin derivative melts atabout 211 to 212 centigrade. The formation of the new body is indicatedin the equations:

in one hundred and thirty parts of hot water,

and the solution thus formed is boiled in a reflux apparatus, whichinduces evolution and escape of carbon dioxid. After this evolution hasceased the liquid is concentrated somewhat (to about one-fourth of itsbulk) and then allowed to cool. After cooling, theobromin cystallizesout of the solution and may be obtained in a pure condition byrecrystallizing from water. The reaction taking place is indicated bythe equation:

method of its manufacture, was'invented by the inventor of thisapplication, said method and its product being described and claimed inthe aforesaid concurrent application, Serial No. 142, 589. In order togive a full disclosure, the method of preparation of this new c'om'pound, though forming no part of the present invention, will now bedescribed.-

Tetramethy'l chlor'o caffein or 8 trichlo' romethy1-7monochl-oromethyl-1, S-dimethyl xanthin having the structural formulaoHiN-oo I CH2; oc C-N 1. 1| c.0013 cHiN-c-N may be prepared by thefollowing method: A solution of one part, by weight, of 8-methylcaffeinin about eight parts, by weight, of nitro benzol is heated on awater-bath and into the so-heated solution a large excess of chlorin gasis introduced untilno more ofthe same is absorbed. Thereupon theuncombined chlorin which remainsdissolved in the nitro-ben- 201 isexpelled as far as possible by introducing or passing over the liquid acurrent of air, whereupon the greater portion of the nitrobenzol isdistilled off from the whole in a vacuum. The residue is then allowed tocool, whereupon the new compound, the 8-trichloro methyl 7 chloromethyl1, 3 dimethyl- Xanthin, is thrown out in the form of coarse crystalswhich are in a fairly pure condition without further treatment. For morecomplete purification they are redissolved in hot alcohol, from whichthey separate in the form of large colorless prismatic crystals whichmelt at about 20 1 to 205 centigrade. The new compound is readilysoluble in chloroform, difficultly soluble in hot alcohol.

Preparation 0 f Theophyllz'n.-1f this 8-trichloro methyl 7monochloromethyl 1, 3-,dimethyl-xanthin or tetrachloro-methyl-caflein beboiled with water,the group CH2.CI at the position 7 is split offsimilarly to the process described in United States Patent No. 660,744,dated October 30, 1900, and in' German Patent No. 105,056, and at thesame time the C013 in position 8 is replaced by H, the reactions takingplace according to the equation:

I occ13 cmiv-o-n (Tetrachloromethyl-caffein) (Theophyllin) Theophyllinis thus readily obtained. The

process in 'detail asfollows: One hundred grams'of the8-trichloromethyl-7-monochloro methyl 1,3 dimethylxanthin ortetrachloromethylcaffein are boiled for a period of time. An intenseodor of formic aldehyde will soon arise and the starting productgradually dissolves, while carbon dioxid escapes.

about one-fourth of its bulk by evaporation or. the like.

If, thereupon, the hydrochloric acid generated in the 'so-lutionispartially neutralized until the solution reacts only weakly acid, thetheophyllin will be thrown down in Theyield is Ewart/ ale 3- Prepamtimz0f Cafe Zn from 8- Trich loromethg l cafem.

The starting compound in this case is S-trichloromethyl-caifein,which,together with the process of preparingit, is described and claimed inthe aforesaid application,Serial No.142, 589. Although the method ofpreparing the said trichlororriethyl-caifein forms no part of thepresent invention, the same will now be described for purposes of a fulldisclosure.

Preprwation 0 f 8-Zlichlorowwt/tyl-cafein.

(a) By mecms 0 f chlorin gas. Fifty-five grams of chlorin gas,corresponding to about three molecules, are introduced into a solutionof fifty grams of dry 8-methyl-calfein in two hundred and fifty cubiccentimeters of chloroform free from water, the said solution beingconstantly stirred duringthe introduction of the gas. The solution isthen evaporated to dryness, whereby the trichloro compound is left as aresidue. The reaction proceeds according to the equation:

I o.oo13 CH3.N-CN

The residue is then purified by dissolving in acetic ether andcrystallizing therefrom. The new compound is obtained in white needleshaving a melting-point of about 182 to 18]:

centigrade. Its formula is ascertained to be:

CH3.l| l ([30 CDHJOZN4C13Z. OC C-N.CH3

OHaN (b) By mums of suZfuryZ-chlorid.-Two

hundred and seventy grams of sulfuryl-chlorid are poured orotherwisegradually introduced into a solution of one hundred grams of 8-methyl-caffeinin five hundred cubiccentimetersof chloroform, whichsolution is kept cool with ice'and which is also constantly kept inmotion while the sulfuryl-chlorid is introduced. After all of thesulfuryl-chlorid has been run in and the evolution of hydrochloric acidhas ceased the chloroform, is distilled off. The residual crudeproduct,-the 8- trichloromethyl-calfein, is purified in the mannerdescribed above.

weight, of 8-trichloromethyl-caifein is boiled for a period of time withabout ten parts, by weight, of water. During this time the startingcompound gradually. goes into solution, carbon-dioxid gas coincidentlyescaping in large quantities. After cooling, the generated hydrochloricacid is partially neutralized until it reacts only slightly acid,whereupon the caffein is precipitated out of the solution.

It will be observed that in allof the examples given in illustration ofthis invention the process, considered in its broader aspects, is ahydrolysis of an 8-chloroalkyl-xanthin, and, more specifically, that itconsists in submitting an 8-trichloro-methyl-xanthin to hydrolysis forthe purpose of obtaining a Xanthin derivative or homologue of Xanthin,such as theobromin, theophyllin, or cafiein.

What is, claimed, and desired to be secure by Letters Patent of theUnited States, is

1. The process of making xanthin derivatives which consists insubmitting an 8-chloroalkyl Xanthin to hydrolysis.

2. The process of making Xanthin derivatives which consists insubmitting an 8-chloromethyl Xanthin to hydrolysis.

8. The process of making Xanthin deriva tives which consists insubmitting an 8-trichloro-methyl Xanthin to hydrolysis.

4:. The process which consists in heating an 8-chloro-alkyl Xanthin withwater.

5. The process which consists in heating an 8-chloro-alkyl Xanthin withWater and concentrating the resultant solution.

6. The process which consists in heating an 8-chloroalkyl Xanthin withWater and concentrating the resultant solution, and, finally, partlyneutralizing the hydrochloric acid contained in the solution until thesolution reacts slightly acid.

7 The process which consists in heating an 8-chloro-methyl Xanthin withwater.

8. The process which consists in heating an 8-chloro-methyl xanthin withwater and concentrating the resultant solution.

9. The process which consists in heating an S-chloro-methyl Xanthin withwater and concentrating the resultant solution, and, finally, partlyneutralizing the hydrochloric acid contained in the solution until thesolution reacts slightly acid.

10. The process which consists in boiling an 8-trichloro-methyl xanthinwith water.

11. The process which consists in boiling an 8-trichloro-methyl Xanthinwith water and concentrating the resulting solution.

12. The process which consists in heating an 8-trichloro-alkyl Xanthinwith Water until solution is effected, and, finally, partly neutralizingthe hydrochloric acid contained in the solution until a weak acidreaction takes place.

13. The process which consists in heating an S-trichloro-methyl xanthinwith water until solution is effected and, finally, partly neutralizingthe solution to weak acid reaction.

14:. The process which consists in boiling an 8-trichloro-methyl xanthinwith water until solution is effected, then condensing the solution,and, finally, partly neutralizing the solution to slight acid reaction.

15. The process which consists in boiling an S-triohloro-methyl Xanthinwith water until solution is effected, then condensing the solution, andcooling, and, finally, partly neutralizing the solution to slight acidreaction.

. 16. The process which consists in boiling an 8 trichloro methylxanthin containing the group CH.2Gl in the position 7 with water untilsolution is effected, then further heating the solution until theformaldehyde has substantially all escaped.

17. The process which consists in boiling an 8 trichloro methyl Xanthincontaining the group CH.2Cl in the position 7 with water until solutionis effected, then further heating the solution until the formaldehydehas substantially all escaped, then condensing the solution, and,finally, partly neutralizing the so-.

